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Short and long term effects of tibolone in postmenopausal women

  • Review
  • Intervention

Authors

  • Giulio Formoso,

    Corresponding author
    1. CeVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena Local Health Authority, Emilia Romagna Regional Health System, Modena, Italy
    • Giulio Formoso, CeVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena Local Health Authority, Emilia Romagna Regional Health System, Viale Muratori 201, Modena, 41124, Italy. g.formoso@ausl.mo.it.

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  • Enrica Perrone,

    1. CeVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena Local Health Authority, Emilia Romagna Regional Health System, Modena, Italy
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  • Susanna Maltoni,

    1. Emilia-Romagna Region, Regional Agency for Health and Social Care, Bologna, Italy
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  • Sara Balduzzi,

    1. University of Modena and Reggio Emilia, Statistics Unit, Department of Oncology, Hematology and Respiratory Diseases, Modena, Italy
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  • Roberto D'Amico,

    1. University of Modena and Reggio Emilia, Statistics Unit, Department of Oncology, Hematology and Respiratory Diseases, Modena, Italy
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  • Chiara Bassi,

    1. CeVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena Local Health Authority, Emilia Romagna Regional Health System, Modena, Italy
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  • Vittorio Basevi,

    1. CeVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena Local Health Authority, Emilia Romagna Regional Health System, Modena, Italy
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  • Anna Maria Marata,

    1. CeVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena Local Health Authority, Emilia Romagna Regional Health System, Modena, Italy
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  • Nicola Magrini,

    1. CeVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena Local Health Authority, Emilia Romagna Regional Health System, Modena, Italy
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  • Emilio Maestri

    1. CeVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena Local Health Authority, Emilia Romagna Regional Health System, Modena, Italy
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Abstract

Background

Tibolone is an option available for the treatment of menopausal symptoms, based on short-term data on its efficacy. However, there is a need to consider the balance between the benefits and risks of tibolone as there are concerns about breast and endometrial cancer as well as stroke.

Objectives

To evaluate the effectiveness and safety of tibolone in treating postmenopausal women.

Search methods

We searched the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register (19 April 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, 2nd Quarter), MEDLINE (from inception to 19 April 2011), EMBASE (1980 to week 3 April 2011), PsycINFO (1806 to week 3 April 2011), Clinical Trials.gov (30 April 2011). Individual researchers and the current manufacturer of tibolone were contacted to identify unpublished and ongoing trials.

Selection criteria

Randomised controlled trials (RCTs) that compared tibolone versus placebo, estrogens or combined hormone replacement therapy (HT) by assessing the percentage of women with menopausal symptoms, the severity of those symptoms and the occurrence of safety outcomes in postmenopausal women.

Data collection and analysis

Four review authors independently extracted information from the articles, resolving discrepancies by consensus. All outcomes studied were dichotomous. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using the random-effects model. Heterogeneity of studies was taken into account before deciding to combine the data.

Main results

When compared to placebo, tibolone was more effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 847; OR 0.42, 95% CI 0.25 to 0.69), although only the 2.5 mg/day dose of tibolone was significantly better than placebo; but with increased vaginal bleeding (seven RCTs, n = 7462; OR 2.75, 95% CI 1.99 to 3.80). When compared to equipotent doses of combined HT, tibolone reduced vaginal bleeding (15 RCTs, n = 6342; OR 0.32, 95% CI 0.24 to 0.42) but was less effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 545; OR 4.16, 95% CI 1.50 to 11.58).

As for long term safety, two major RCTs of tibolone versus placebo provided the most relevant data. An RCT of 3098 women with breast cancer and menopausal symptoms was halted after 3.1 years because of increased tumour recurrence (OR 1.50; 95% CI 1.21 to 1.85). However, in another RCT that selected osteoporotic women with negative mammograms (n = 4506) tibolone was associated with a reduction in breast cancer compared to placebo after 2.8 years (OR 0.32, 95% CI 0.13 to 0.79) although the trial was not specifically designed to assess that outcome and the number of overall events was low. In the same RCT, an excess risk of stroke was observed (OR 2.18, 95% CI 1.12 to 4.21). There was no clear evidence of a tibolone effect on endometrial cancer compared with placebo given the low number of events (seven RCTs, n = 8152; OR 1.98, 95% CI 0.73 to 5.32).

There was no evidence of a difference in long term safety between tibolone and combined HT.

Authors' conclusions

Tibolone, used at the daily dose of 2.5 mg, may be less effective than combined HT in alleviating menopausal symptoms although it reduced the incidence of vaginal bleeding. There was evidence that treatment with combined HT was more effective in managing menopausal symptoms than was tibolone. Available data on the long term safety of tibolone is concerning given the increase in the risk of breast cancer in women who had already suffered from breast cancer in the past and in a separate trial the increase in the risk of stroke in women whose mean age was over 60 years. Similar concerns may exist for estroprogestins but their overall benefit-risk profile is better known and is more directly related to women with menopausal symptoms.

Résumé scientifique

Effets à court et à long terme de la tibolone chez la femme ménopausée

Contexte

La tibolone est une option envisageable pour le traitement des symptômes de la ménopause, d'après les données disponibles sur son efficacité à court terme. Cependant, il convient de pondérer les bénéfices et les risques de la tibolone car sa possible influence sur les cancers du sein et de l'endomètre ainsi que sur les AVC est préoccupante.

Objectifs

Évaluer l'efficacité et l'innocuité de la tibolone dans le traitement des femmes ménopausées.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre spécialisé du groupe Cochrane sur les troubles menstruels et de la fertilité (le 19 avril 2011), dans le registre Cochrane des essais contrôlés (CENTRAL) (The Cochrane Library 2011, 2ème trimestre), MEDLINE (des origines au 19 avril 2011), EMBASE (de 1980 à la 3ème semaine d'avril 2011), PsycINFO (de 1806 à la 3ème semaine d'avril 2011) et Clinical Trials.gov (30 avril 2011). Nous avons contacté certains chercheurs ainsi que le fabricant actuel de la tibolone afin d'identifier des essais non publiés ou en cours.

Critères de sélection

Des essais contrôlés randomisés (ECR) ayant comparé la tibolone à un placebo, aux œstrogènes ou à l'hormonothérapie substitutive combinée, à travers l'évaluation du pourcentage de femmes présentant des symptômes ménopausiques, de la gravité de ces symptômes et de l'apparition de problèmes de non-innocuité chez les femmes ménopausées.

Recueil et analyse des données

Quatre auteurs ont extrait de façon indépendante les informations des articles, les divergences étant résolues par consensus. Tous les résultats étudiés étaient dichotomiques. Les rapports des cotes (RC) et les intervalles de confiance (IC) à 95 % ont été calculés au moyen du modèle à effets aléatoires. L'hétérogénéité des études a été prise en compte avant de décider de regrouper des données.

Résultats principaux

En comparaison avec le placebo, la tibolone était plus efficace pour atténuer la fréquence des symptômes vasomoteurs (deux ECR ; n = 847 ; RC 0,42 ; IC à 95 % 0,25 à 0,69), bien que seule la dose de 2,5 mg/jour de tibolone fut significativement meilleure que le placebo, mais avec une augmentation des saignements vaginaux (sept ECR ; n = 7 462 ; RC 2,75 ; IC à 95 % 1,99 à 3,80). En comparaison avec des doses équipotentes d'hormonothérapie combinée, la tibolone réduisait les saignements vaginaux (15 ECR ; n = 6 342 ; RC 0,32 ; IC à 95 % 0,24 à 0,42), mais était moins efficace pour atténuer la fréquence des symptômes vasomoteurs (deux ECR ; n = 545 ; RC 4,16 ; IC à 95 % 1,50 à 11,58).

Pour ce qui concerne la sécurité à long terme, deux ECR majeurs de la tibolone versus placebo ont fourni les données les plus pertinentes. Un ECR portant sur 3 098 femmes souffrant du cancer du sein et de symptômes ménopausiques a été arrêté après 3,1 années en raison de l'augmentation des cas de récidive tumorale (RC 1,50 ; IC à 95 % 1,21 à 1,85). Toutefois, dans un autre ECR qui avait sélectionné des femmes ostéoporotiques ayant une mammographie négative (n = 4 506), la tibolone était associée à une réduction du cancer du sein comparativement au placebo après 2,8 années (RC 0,32 ; IC à 95 % 0,13 à 0,79), bien que l'essai n'ait pas été spécifiquement conçu pour évaluer ce critère de résultat et que le nombre total d'événements fut faible. Dans le même ECR, un risque accru d'accident vasculaire cérébral avait été observé (RC 2,18 ; IC à 95 % 1,12 à 4,21). Par rapport au placebo, il n'y avait aucune preuve claire d'un effet de la tibolone sur le cancer de l'endomètre, étant donné le faible nombre d'événements (sept ECR ; n = 8 152 ; RC 1,98 ; IC à 95 % 0,73 à 5,32).

Aucune preuve de différence en matière d'innocuité à long terme entre la tibolone et l'hormonothérapie combinée n'a été observée.

Conclusions des auteurs

La tibolone, en dose quotidienne de 2,5 mg, pourrait être moins efficace que l'hormonothérapie combinée pour alléger les symptômes ménopausiques mais elle a permis de réduire l'incidence des saignements vaginaux. Des résultats montraient que le traitement par hormonothérapie combinée était plus efficace pour la gestion des symptômes ménopausiques que la tibolone. Les données disponibles sur l'innocuité à long terme de la tibolone sont préoccupantes en raison de l'augmentation du risque de cancer du sein chez les femmes ayant déjà souffert d'un cancer du sein dans le passé et, dans un autre essai, de la hausse du risque d'AVC chez les femmes dont l'âge moyen était supérieur à 60 ans. Des préoccupations similaires pourraient exister pour les estroprogestatifs, mais leur profil bénéfice-risque global est mieux connu et plus directement lié aux femmes ayant des symptômes ménopausiques.

Resumo

Efeitos a curto e longo prazo da tibolona em mulheres na pós-menopausa

Introdução

Tibolona é uma opção disponível para o tratamento dos sintomas da menopausa, com base em dados de curto prazo sobre a sua eficácia. No entanto, há uma necessidade de considerar o balanço entre os benefícios e riscos da tibolona uma vez que existem preocupações sobre câncer de mama e endométrio, bem como acidente vascular cerebral.

Objetivos

Avaliar a eficácia e segurança da tibolona no tratamento de mulheres na pós-menopausa.

Métodos de busca

Pesquisamos na Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register (19 de Abril de 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, segundo quarto), MEDLINE (desde o início até 19 de Abril de 2011), EMBASE (1980 até a semana de 3 April 2011), PsycINFO (1806 até a semana de 3 April 2011), Clinical Trials.gov (30 de Abril de 2011). Pesquisadores individuais e o fabricante atual de tibolona foram contatados para identificar ensaios clínicos não publicados e em andamento.

Critério de seleção

Ensaios clínicos randomizados (ECR) que compararam tibolona versus placebo, estrógenos ou terapia de reposição hormonal combinada (TH) avaliando a porcentageml de mulheres com sintomas da menopausa, a severidade desses sintomas e a ocorrência de achados de segurança em mulheres na pós-menopausa

Coleta dos dados e análises

Quatro revisores extraíram independentemente as informações dos artigos, resolvendo as discrepâncias por consenso. Todos os desfechos estudados eram dicotômicos. Odds ratio (OR) e intervalo de confiança (IC) de 95% foram calculados usando o modelo de efeitos aleatórios. Heterogeneidade dos estudos foi levada em conta antes de decidir combinar dados.

Principais resultados

Em comparação ao placebo, a tibolona foi mais eficaz no alívio da frequência dos sintomas vasomotores (dois ECRs, n = 847; OR 0,42, IC 95% 0,25-0,69), embora apenas a dose de 2,5 mg/dia de tibolona tenha sido significativamente melhor que o placebo; mas com aumento na incidência de sangramento vaginal (sete ECR, n = 7462; OR 2,75, IC 95% 1,99-3,80). Quando comparada a doses equipotentes de HT combinada, a tibolona reduziu o sangramento vaginal (15 ECRs, n = 6.342, ou 0,32, IC 95% 0,24-0,42), mas foi menos eficaz no alívio da frequência dos sintomas vasomotores (dois ECRs, n = 545; OR 4,16, IC 95% 1,50-11,58).

Quanto a segurança a longo prazo, dois grandes ECRs com tibolona versus placebo forneceram os dados mais relevantes. Um ECR com 3.098 mulheres com câncer de mama sintomas da menopausa foi interrompido depois de 3,1 anos devido ao aumento da recorrência do tumor (OR 1,50; IC 95% 1,21-1,85). No entanto, em outro ECR que incluiu mulheres osteoporóticas com mamografias negativas (n = 4.506) a tibolona foi associada com uma redução na incidência do câncer de mama, em comparação com o placebo, após 2,8 anos (OR 0,32, IC 95% 0,13-0,79), embora o ensaio não foi especificamente desenhado para avaliar esse resultado e o número global de eventos foi baixo. No mesmo ECR, um excesso de risco de acidente vascular cerebral foi observado. (OR 2,18, IC 95% 1,12-4,21). Não houve nenhuma evidência clara do efeito da tibolona sobre o câncer endometrial comparado com placebo dado o baixo número de eventos (sete ECRs, n = 8.152; OR 1,98, IC 95% 0,73-5,32).

Não houve evidência na diferença, a longo prazo, em segurança entre a tibolona e TH combinada.

Conclusão dos autores

Tibolona, na dose diária de 2,5 mg, pode ser menos eficaz do que a TH combinada no alívio dos sintomas da menopausa, embora tenha reduzido a incidência de sangramento vaginal. Há evidência de que o tratamento com a TH combinada foi mais eficaz para o controle dos sintomas da menopausa que a tibolona. Os dados disponíveis sobre a segurança em longo prazo da tibolona é relativa, dado o aumento no risco de de câncer de mama em mulheres que já sofreram de câncer de mama no passado, e em um ensaio clínico separado, o aumento do risco de acidente vascular encefálico em mulheres com idade média maior que 60 anos. Preocupações semelhantes podem existir para a terapia estroprogestina mas o seu perfil geral de risco-benefício é mais conhecido e está mais diretamente relacionada com as mulheres com sintomas da menopausa.

Notas de tradução

Traduzido por: Lucia alves S Lara, Unidade de Medicina Baseada em Evidências da Unesp, Brazil Contato: portuguese.ebm.unit@gmail.com

Plain language summary

Combined hormone therapy is more effective than tibolone on menopausal symptoms. Tibolone may increase the risk of recurrent breast cancer and stroke

The authors analysed 33 clinical trials to evaluate whether tibolone, compared to placebo or combined hormone replacement therapy (HT), was effective in alleviating menopausal symptoms and the risks associated with the longer term use of HT. Limited evidence suggested that tibolone was less effective than combined HT in the treatment of menopausal symptoms, although fewer women suffered vaginal bleeding. In two separate trials, prolonged use of tibolone (for one or more years) increased the risk of breast cancer in women who had already suffered from breast cancer in the past and increased the risk of stroke in women whose mean age was over 60 years. The risk profile of this drug is not well defined but it is concerning enough that its longer term use should not be supported.

Résumé simplifié

L'hormonothérapie combinée est plus efficace que la tibolone sur les symptômes ménopausiques. La tibolone pourrait augmenter le risque d'accident vasculaire cérébral (AVC) et de récurrence du cancer du sein

Les auteurs ont analysé 33 essais cliniques afin d'évaluer si la tibolone, en comparaison avec un placebo ou avec un traitement hormonal substitutif combiné, était efficace pour soulager les symptômes de la ménopause et réduire les risques associés à l'utilisation de l'hormonothérapie sur le long terme. Des résultats de portée limitée ont suggéré que la tibolone était moins efficace que l'hormonothérapie combinée dans le traitement des symptômes de la ménopause, bien que moins de femmes aient souffert de saignements vaginaux. Dans deux essais distincts, l'utilisation prolongée de la tibolone (pendant une ou plusieurs années) avait augmenté le risque de cancer du sein chez les femmes ayant déjà souffert de ce cancer dans le passé ainsi que le risque d'accident vasculaire cérébral chez les femmes dont l'âge moyen était de plus de 60 ans. Le profil de risque de ce médicament n'est pas bien défini, mais il parait suffisamment inquiétant pour que son utilisation à long terme ne soit pas encouragée.

Notes de traduction

Traduit par: French Cochrane Centre 18th May, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Resumo para leigos

Terapia hormonal combinada é mais eficaz do que tibolona sobre sintomas da menopausa. Tibolona pode aumentar o risco de câncer de mama recorrente e acidente vascular cerebral.

Os autores analisaram 33 ensaios clínicos para avaliar se a tibolona, comparada com placebo ou com a terapia de reposição hormonal combinada (HT), foi eficaz no alívio dos sintomas da menopausa e dos riscos associados com o uso prolongado de TH. Evidência limitada sugere que a tibolona é menos eficaz do que a TH combinada no tratamento dos sintomas da menopausa, no entanto, menos mulheres tiveram sangramento vaginal. Em dois ensaios clínicos separados, o uso prolongado de tibolona (por um ano ou mais) aumentou o risco de câncer de mama em mulheres que já tinham sofrido de câncer de mama no passado e aumentou o risco de acidente vascular cerebral em mulheres cuja média de idade era 60 anos. O perfil de risco dessa droga não está bem definido, mas é preocupante o suficiente para que o seu uso a longo prazo não seja apoiado.

Notas de tradução

Traduzido por: Lucia alves S Lara, Unidade de Medicina Baseada em Evidências da Unesp, Brazil Contato: portuguese.ebm.unit@gmail.com

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